Members of the peroxisome proliferator-activated receptors (PPARs) regulate important transcriptional programs to maintain metabolic homeostasis and as such are current and prospective therapeutic targets to treat metabolic diseases. Our long-term goal is to understand the regulatory mechanisms in each of the metabolically active tissues through which PPAR? (also referred to as PPAR?) controls metabolism. Previous studies have suggested that this receptor increases fatty acid ?-oxidation in peripheral tissues to prevent diet-induced obesity. Using mouse models of insulin resistance, our results have identified the liver as an additional site of PPAR? action in regulating glucose and fatty acid metabolism as well as insulin sensitivity. In contrast to its activity in the periphery, we found that PPAR? activation lowers glucose levels through regulation of glucose utilization pathways, including glycogen and fatty acid synthesis. The hypothesis behind this proposal is that PPARd plays an important role in controlling hepatic lipid and carbohydrate metabolism through a three-step energy substrate switching mechanism, in which it promotes glucose utilization in liver for the synthesis of glycogen and fatty acids. The newly made lipids are subsequently delivered by VLDL and utilized in the periphery. The specific aims are designed to determine the molecular mechanisms by which PPAR? regulates these processes, which should identify novel therapeutic pathways to control the progression of metabolic diseases, such as insulin resistance.